Primary sclerosing cholangitis (PSC) is a progressive chronic cholestatic liver disease of unknown etiology. Characterized by inflammation and destruction of bile ducts, PSC often progresses to advanced live disease such as cirrhosis, hepatobiliary cancer and liver failure. Without an effective therapeutic option, liver transplantation is currently considered the only curative option for PSC and results an excellent 5 year survival rate of 86% in PSC patients. However, the optimal timing for liver transplantation is difficult to determine due to high risk of PSC-associated hepatobiliary malignancies. The progression of PSC is commonly monitored by Endoscopic Retrograde Cholangiopancreatography (ERCP) and liver biopsy; invasive procedures associated with increased risk of serious complications. Thus, a non-invasive tool to monitor the progression of PSC remains an unmet medical need. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression by pairing with partially complementary target sequences in the 3' untranslated regions of messenger RNAs (mRNAs) to promote mRNA degradation and/or block translation. Recent studies have shown that levels of many circulating serum miRNA are elevated in patients with a variety of liver diseases and pathologies including HCC, HBV and liver cirrhosis. Therefore serum miRNAs represent a new type of diagnostic and prognostic biomarker for several liver diseases. Although serum miRNA biomarkers for PSC have not been developed for clinical use, our preliminary proof-of-concept study identified subsets of serum miRNA signatures that have unique expression patterns in PSC progression and associated complications. Here, we propose to validate these initial results in a larger independent PSC cohort and confirm the relationship of the serum miRNA signatures to miRNA and target gene expression in the liver using cutting-edge next-generation RNA-seq technologies. We will confirm the sensitivity and specificity of serum PSC miRNA biomarkers released from diseased liver to predict advanced PSC in an appropriately powered study. The proposed studies are feasible, represent two critical steps in developing novel biomarkers for clinical use for PSC diagnosis and prognosis, and provide a unique opportunity to identify new mechanisms involved in PSC-progression and the development of PSC associated hepatobiliary malignancies.